Rheumatoid arthritis, as a clinical disease, but not rheumatoid arthritis-associated autoimmunity, is linked to cardiovascular events

Rheumatoid arthritis (RA) is an autoimmune chronic inflammatory disease characterized by synovitis leading to joint destruction and functional impairment [1]. Prevalence of RA is around 0.5% in Caucasian population [2]. RA development is promoted by a combination of genetic susceptibility and environmental factors that leads to breech of immune tolerance and formation of autoantibodies such as rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA) [1]. Autoimmunity precedes RA by several years (positive predictive value > 96% at 5 years) [3‐5] and is associated with higher disease activity and structural damage [6, 7].

RA is characterized by an increased morbidity and mortality [8‐11]. Besides structural damage and its consequences on disability, increased cardiovascular (CV) risk, including myocardial ischemia and heart failure, has been described in RA [10]. Aside from the consequences from disability and infections, CV disease is responsible for increased mortality in RA [8‐11]. Increased CV risk in RA does not only seem to be explained by standard CV risk factors, but also by chronic inflammation, which accelerates the process of atherosclerosis [12, 13]. This process seems to be independent from the use of concomitant treatments such as corticosteroids or non-steroidal anti-inflammatory drugs (NSAIDs), which also add to CV risk [14].

In recent years, several studies suggested that RA with positive RF and/or ACPA presents a higher CV risk [9, 15‐18]. Thus, one may think that RF and ACPA could influence CV risk independently from RA. However, evidence that CV disease may be linked to the presence of autoantibodies, independently from the occurrence of RA, is scarce, and only one study suggested that autoimmunity increases CV risk [15, 16, 19] in a subpopulation of African-American women, but not in all women with positive RF or ACPA [19]. To further explore this question, we made use of a large epidemiological cohort [20‐22] and separately tested the influence of RA on CV risk as well as the impact of autoantibodies (RF/ACPA) on CV risk, independently of the presence of RA.

In this study, we found that RA, as a clinical disease, but not RA-related autoimmunity was associated with CV events. It is known that RA is associated with two-fold increased risk for CV disease as compared to the general population [24‐26]. While the overall CV risk in RA patients is based on traditional risk factors as well as autoimmunity related to RA, the increased risk due to RA is usually considered to be due to an increased inflammation and/or autoimmunity [24]. While systemic markers of inflammation have shown to be associated with a higher CV risk [27], other studies have also reported that CV risk is higher in RA patients with ACPA positivity [15‐18], but such observation could be also explained by the correlation between ACPA positivity and RA severity [28], rather than by an independent association with ACPA. Hence, in the RA population, disentangling the effect of autoimmunity on CV risk from that of inflammation is difficult, if not impossible.

The fact that ACPA and RF positivity precedes RA and that some individuals are positive for RF or ACPA without even developing the disease allows to separately assess the role of RA-related autoimmunity and RA, as an inflammatory joint disease, on CV risk [4‐6]. The analysis of GAZEL individuals that were positive for RF and/or ACPA permitted to directly evaluate the association between ACPA/RF and CV without the influence of arthritis. However, the analysis of these subjects was limited because of the rather low number of subjects with available blood sample, as compared to the whole cohort. Nevertheless, our analysis suggested that RA-related autoimmunity was not associated with an increased risk for CV disease, indicating that systemic inflammation is likely required for precipitating CV events. Under this hypothesis, it is conceivable that effector function of autoantibodies, i.e., Fc- mediated cytokine release, which translates asymptomatic autoimmunity to inflammatory disease might be critical for conveying CV risk [29].

In the GAZEL cohort, traditional risk factors such as male sex, age smoking, hypertension, hyperlipidemia, and diabetes mellitus were independently associated with CV events. Notably, the presence of RA also was significantly associated with CV disease with a HR of 3.0. The strength of the association between CV events and RA is reflected by the fact that the number of ascertained RA cases was rather low in this cohort but nonetheless this association was robust. This observation also supports the robustness of the lack of association between autoantibodies and CV risk as the numbers of autoantibody positive subjects was much higher than the one with RA. The overall low number of ascertained RA cases can be explained by the fact that participants of the GAZEL cohort were mostly males (> 70%). Considering a prevalence of RA of 0.5% in the French population [2], that only up to 1/3 of RA patients being males and that not all subjects with self-reported RA could be validated, the numbers of observed and established RA cases fits the numbers of expected RA cases.

Strength of this study includes the fact that the increased risk of CV events in RA patients as compared to controls was objectively confirmed and that the associations between RA and CV events on one hand, and autoantibodies and CV events in the other were assessed in the same cohort. Another strength is that the ascertainment of RA cases did not rely merely on self-reporting but was confirmed by experienced rheumatologist, using a dedicated questionnaire that was developed and validated for this purpose. A previous study assessed the association between autoantibodies and CV risk in a population-based cohort [30] and found that RF was a predictor of CV events. In this study, there was a higher number of subjects, but RA diagnosis was not confirmed by phone consultation, and CV comorbidities were analyzed only according to baseline characteristics. Concerning ACPA, only a part of the cohort was tested (N = 299), and the association between ACPA and CV events was not adjusted on rheumatic disease. Another study assessing the association between ACPA and RF and CV risk in non-RA patients found that the presence of autoantibodies was associated with CV risk increased in African American women, but the diagnosis of RA was again only based on self-reporting information [19]. A limitation of our study is due to the fact that plasma samples were not available in the entire GAZEL cohort and hence autoantibody data were only obtained in a fraction of the cohort. The fact that we found no significant association between RF and/or ACPA and CV events indicates however that there was no strong association between autoimmunity and CV risk, but does not formally allow to conclude to the absence of such association, considering the rather limited sample-size. On the other hand, subjects with plasma available did not essentially differ from the others with respect to demographic characteristics, CV risk factors and CV events. Furthermore, the robustness of a lack of association between autoantibodies and CV events is supported by the fact that positive association could be observed for RA, despite the fact that the number of RA cases was substantially lower than the number of subjects positively tested for autoantibodies. Finally, as the GAZEL cohort had a high ratio of men, and included subjects with a restricted age range, further studies including a larger number of subjects and a larger women representativeness will be needed to validate our results.

These data suggest that CV risk in RA may rather be dependent on the inflammatory disease itself, while the mere presence of RA-related autoimmunity may not be associated, alone, with CV disease. Thus, the higher risk for CV events in autoantibody-positive RA may be related to a more severe and chronic course of the disease rather than direct effects of autoantibodies on the vessels. These data support the observations that effective control of inflammation may lower CV risk [31, 32].